Figure 1: Electrical Conduction System of the Heart
Many medications, including potassium-sparing diuretics, ACE inhibitors, and some of the newer nonsedating antihistamines, can cause variations in ECG results. Consultant pharmacists who recognize the potential for drug-induced changes in ECG readings of elderly nursing home residents can provide useful information to help the interdisciplinary care team optimize patient care.
Many elderly persons take multiple pharmacologic agents, which may alter membrane function and lead to drug-induced changes in electrocardiogram results. Learning to recognize these potential medication- related changes in ECG results can help the consultant pharmacist and the health care team interpret test results correctly and home in on early signs of toxicity in elderly individuals with altered metabolism or impaired elimination.
Electrical Conduction and the Heart
Figure 1: Electrical Conduction System of the Heart
The electrical conduction system of the heart, which produces the electrical activity measured by the electrocardiogram, is composed of the sinoatrial (SA) node, the internodal and interatrial conduction tracts, the atrioventricular (AV) junction (consisting of the atrioventricular node and the bundle of His), the right and left bundle branches, and the Purkinje fibers (see Fig. 1).
In the resting state, cardiac muscle cells are polarized due to gradients established by the active inward transport of potassium ions and the outward transport of sodium ions. Various stimuli-including drug-induced effects-can cause shifts in these gradients, producing a decrease in the internal negative membrane potential. This process is known as depolarization.
The sinoatrial node, located at the junction of the superior vena cava and the right atrium, is the area of the heart which, under normal conditions, depolarizes most rapidly. The specialized tissue in the sinoatrial node consists of cells that generate electrical current automatically and regularly. Thus, the sinoatrial node is often referred to as the pacemaker of the heart. Each electrical impulse travels from the sinoatrial (SA) node through the right atrium via three internodal atrial conduction tracts to the atrioventricular (AV) node, located at the proximal part of the atrioventricular junction.
The interatrial conduction tract, also referred to as Bachmann's bundle, branches off one of the internodal atrial tracts and extends across the atria, relaying the impulse from the right to left atrium.
Once the wave of depolarization reaches the AV node, there is a delay that allows the atria to contract, thus emptying blood into the ventricles before the ventricles are stimulated to contract. During this time, electrical activity moves very slowly from the atrium into and through the AV node and into the proximal portions of the ventricular conduction system, the bundle of His, and the bundle branches. Depolarization spreads along the ventricular conduction system (the distal bundle branches and Purkinje fibers) first through the septum, then through the apex and into the bulk of the left and right ventricular walls.
The muscle cells of the heart form a syncytium; that is, they are joined in a way that enables electrical activity to move quickly and easily from one cell to the next. The depolarization of each cardiac cell acts as an electrical impulse on adjacent cells, causing them to depolarize. It is this propagation of electrical impulse from cell to cell that produces waves of depolarization that can be measured as an electric current flowing in the direction of depolarization.
As the cells repolarize, another electric current is produced, similar to the first but moving in the opposite direction. The magnitude and direction of the electrical activity occurring during depolarization and repolarization can be detected by electrodes attached to the skin; this information is then amplified and displayed on the ECG as waves and complexes.
The current generated by the atrial depolarization is recorded as the P wave, and that generated by the ventricular depolarization is recorded as Q, R, and S waves, collectively called the QRS complex. Atrial repolarization and ventricular repolarization, which generally occur simultaneously, are recorded as the T wave.
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| Figure 2: Electrical Basis of the Electrocardiogram |
Figure 3: Components of the Electrocardiogram |
In a normal cardiac cycle, the P wave occurs first, followed by
the QRS complex and the T wave. The U wave, which represents the
final phase of repolarization, is often superimposed on the T
wave (see fig. 2 and 3).
The sections of the ECG between the waves and complexes are called segments and intervals. Intervals include waves and complexes, while segments do not. For example, we speak of the PR segment, the ST segment, the PR interval, the QT interval, and the R-R interval.
When electrical activity of the heart is not being detected, the ECG is a straight, flat line, called the isoelectric line, or baseline. 2
Hyperkalemia and ECG Results
Several different types of drugs-most notably potassium-sparing diuretics and ACE inhibitors-can cause hyperkalemia, which can produce significant changes in the ECG. In elderly persons, a decline in renal function may also lead to hyperkalemia.
Characteristic ECG changes occur at various levels of hyperkalemia. The QRS complexes begin to widen when the patient's serum potassium level reaches about 6-6.5 mEq/L, becoming markedly slurred and abnormally widened at 10 mEq/L.
Figure 4: Hyperkalemia
The QRS complexes may widen so that they merge with the T waves, resulting in a "sine wave" appearance. The ST segments disappear when the serum potassium level reaches 6 mEq/L and the T waves typically become tall and peaked at this same range. The P waves begin to flatten out and widen when a patient's serum potassium level reaches about 6.5 mEq/L; this effect tends to disappear when levels reach 7-9 mEq/L. Sinus arrest may occur when the serum potassium level reaches about 7.5 mEq/L, and cardiac standstill or ventricular fibrillation may occur when serum levels reach 10 to 12 mEq/L 2 (See fig. 4).
Changes Caused by Hypokalemia
Hypokalemia can commonly result from the loss of potassium through dehydration, vomiting, gastric suction, or excessive diuretic use. The thiazide and loop diuretics are most commonly implicated in the development of hypokalemia.
Figure 5: Hypokalemia
Symptoms of hypokalemia range from polyuria in mild cases to muscle weakness in more severely affected patients. On the ECG, the QRS complexes begin to widen when the serum potassium drops to about 3 mEq/L, the ST segments may become depressed, and the T waves may begin to flatten. The U waves also begin to increase in size, becoming as tall as the T waves. The U waves reach "giant" size and fuse with the T waves when the level drops to 1 mEq/L 2 (See fig. 5).
Figure 6: Hypercalcemia and Hypocalcemia
Calcium
Alterations in serum calcium levels may also produce serious arrhythmias,
leading to alterations in ECG results. Hypocalcemia, which may
be caused by loop diuretics, osteomalacia, hypoparathyroidism,
or respiratory alkalosis, may produce prolongation of the ST segment
and QT interval. Hypercalcemia, caused by adrenal insufficiency,
hyperparathyroidism, kidney failure, or malignancy, may also cause
serious arrhythmias, especially in the presence of digitalis 2
(See fig. 6).
Figure 7: Digitalis Effect
Digitalis
The administration of digitalis can cause ECG changes, even when the dosage is within the recommended therapeutic range. In cases of digitalis toxicity, excitatory or inhibitory effects on the heart and its electrical conduction system may occur. Excitatory effects include various types of ventricular and supraventricular ectopy, ventricular tachycardia, and ventricular fibrillation. Inhibitory effects include sinus bradycardia and heart block. The digitalis effect produces prolonged PR intervals, depressed (scooped) ST segments, and alterations in T wave morphology (See fig. 7).
Phenothiazines
The electrophysiological properties of phenothiazines are comparable to those of the Class Ia antiarrhythmic quinidine. Numerous ECG aberrations may be induced by these agents, including changes in the morphology of the T wave, prolongation of the QT interval, and accentuation of the U wave.
"These repolarization abnormalities occur more frequently with thioridizine than with chlorpromazine, and even less so with trifluoperazine," wrote Symanski and Gettes in the February 1993 issue of Drugs.1 "Supraventricular and ventricular tachycardias have been reported in patients receiving high doses of phenothiazines. Even with standard clinical dosages (100-400 mg/day), thioridazine causes minimal prolongation of the QT interval, reduction of T wave amplitude, and prominent U waves in nearly 50 percent of patients."
Antidepressants
At either therapeutic or toxic dosages, tricyclic and tetracyclic antidepressants can produce a number of effects on the ECG. ECG Changes produced by TCAs occur in about 20 percent of patients receiving therapeutic dosages and include an increase in heart rate, prolongation of the PR interval, intraventricular conduction disturbances, increase in QTc interval, and flattening of T waves. Factors such as the specific agent, plasma drug concentration, duration of therapy, age of the patient, and degree of underlying cardiovascular disease all play a role in the severity and frequency of these effects. While the risk of ventricular arrhythmia has been shown to correlate poorly with serum TCA concentrations, the electrocardiogram may still be a useful tool in detecting patients with suspected TCA overdose. 1
Antihistamines
Stimulation of histamine receptors (H1 and H2), which are located in both the atrial and ventricular myocardium and on epicardial coronary arteries, may also produce changes on the ECG. Stimulation of the H2 receptors in the atrial and ventricular myocardium raises intracellular concentrations of cAMP by activating adenylate cyclase and phosphorylase, resulting in enhanced inotropic and chronotropic effects. Thus, the blocking of H2 receptors by the H2 antagonists may result in bradyarrhythmias, as noted in several case reports in which cimetidine and ranitidine have been implicated as rare causes of sinus bradycardia and heart block. The risk of these complications appears to be greater with long-term therapy and among elderly individuals.1
The newer, long-acting, nonsedating antihistamines such as terfenadine and astemizole can pose a threat of cardiotoxicity. Rare reactions have occurred when blood levels of these agents become elevated due to either overdose or inhibition of their metabolism when given concomitantly with other agents (erythromycin, ketoconazole, or, as has been recently reported, grapefruit juice) affecting the same CP450 isozyme.
The disturbance in cardiac conduction is thought to be caused by these agents' ability to block the potassium channel in the myocardial cell membrane, which affects cardiac repolarization. Thus, the effect on the ECG is prolongation of the QT interval, which may lead to torsade de pointes (see glossary). Studies to date have found no similar threat of cardiotoxicity with loratidine and cetirizine. 4
Other Drug Influences
The electrocardiographic effects of catecholamines, including agents such as dopamine and epinephrine, can be problematic to predict, since these agents have numerous effects on the heart. Catecholamines affect the currents that regulate repolarization of individual cells and fibers, and also can affect the heart rate, blood pressure, and serum potassium levels.
ECG changes caused by catecho-lamines are influenced by the route and rate of administration, as well as the dosage. For example, subcutaneous administration of epinephrine produces only sinus tachycardia and occasional premature beats. However, when administered intravenously, epinephrine may cause a variety of repolarization abnormalities, including ST changes. Intravenous infusion of isoprenaline (isoproterenol), to give another example, may cause inversion of T waves.1
As more and more elderly nursing home residents are treated with a variety of pharmacological agents that affect membrane function and myocardial cells, the ECG is becoming a useful tool for monitoring drug effects and toxicities-not only for the physician, but for the entire interdisciplinary care team, including the consultant pharmacist. An appreciation of the information contained in the ECG printout is an essential component in the continuing effort to provide the best in comprehensive patient care.
References:
1. Symanski, JD, and Gettes, LS. Drug Effects on the Electrocardiogram: A Review of their Clinical Importance; Drugs 46 (2) 219 - 248, 1993.
2. Huszar, Robert: Basic Dysrhythmias: Interpretation and Management; 2nd edition; 1994, Mosby-Year Book, Inc.
3. Scheidt, Stephen. Basic Electrocardiography ECG; Ciba-Geigy Pharmaceuticals, 1986.
4. Scheife, RT, Cramer WR. Sedative and Cardiovascular Profile of Newer Antihistamines. The Consultant Pharmacist, October 1996, pp. 1037-1053.
Glossary of Terms in Electrocardiography
Arrhythmia: Abnormal or irregular rhythm caused by a disturbance in the electrical conduction of the heart.
Artifact: Mechanically or electrically produced extraneous spikes and waves recorded on an ECG. Common causes of artifact are muscle tremor, alternating current (AC) interference, loose electrodes, interference related to biotelemetry, and external chest compression.
Automaticity: The capacity of a cardiac cell to depolarize spontaneously.
Bigeminy: An arrhythmia in which every other beat is a premature contraction. The premature beat may be atrial, junctional, or ventricular in origin.
Bradycardia: Heart rate less than 60 beats per minute.
Chronotropic: Affecting the heart rate.
Diastole: The period during which the atria and ventricles relax, filling with blood.
Ectopy: Extraneous electrical impulses originating from a location other than the primary pacemaker cells of the heart.
Electrocardiogram (ECG or EKG): Record of the electrical activity of the heart.
Electrocardiograph: Machine used to record the ECG.
Fibrillation: Chaotic, disorganized beating of the myocardium in which each myofibril contracts and relaxes independently, producing rapid, tremulous, and ineffectual contractions. Fibrillation may occur in both the atria and the ventricles.
Reentry: Condition in which the progression of an electrical impulse is delayed or blocked (or both) in one or more segments of the electrical conduction system while being conducted normally through the rest of the conduction system.
Gap junction: A structure within the intercalated disks located at the junctions of the branches of myocardial cells, permitting very rapid conduction of electrical impulses from one cell to another.
Inotropic: Affecting the contractility of the myocardium.
P wave: Segment of the ECG produced by depolarization of the atria.
PR interval: Represents the time of progression of the electrical impulse from the pacemaker cell to the ventricular myocardium.
Pacemaker cells: Specialized cells in the cardiac conduction system that have the property of automaticity.
QRS segment: Segment of the ECG produced by depolarization of the ventricles.
QT interval: Measured from the beginning of the QRS complex to the return of the T wave to the baseline; prolongation of the QT interval may lead to ventricular arrhythmias, including torsade de pointes.
QTc interval: Calculation of QT interval with adjustment for heart rate.
Repolarization: Ion exchange process whereby the cardiac cell returns to its resting state.
ST segment: The section of the ECG between the end of the QRS complex and the onset of the T wave; may be flat (horizontal), downsloping, or upsloping.
Systole: The period of atrial or ventricular contraction.
T wave: Segment of the ECG produced by repolarization of the atria.
Tachycardia: Heart rate over 100 beats per minute.
Torsade de pointes: A French expression meaning "twisting around a point" and referring to a form of ventricular tachycardia characterized by QRS complexes that gradually change back and forth from one shape and direction to another over a series of beats.
U wave: The positive wave superimposed on or following the T wave. Possibly represents the final phase of repolarization of the ventricles.
Source: Huszar RJ. Basic dysrhythmias: interpretation and management; 2nd edition; 1994.
EFFECTS OF OTHER AGENTS on ECG Results
| AGENT | MECHANISM | ECG CHANGES |
| Penicillin | Rapid IV administration of the potassium salt may produce ECG changes characteristic of hyperkalemia; anaphylactic reactions also may produce a variety of ECG changes | See hyperkalemia; prominent T waves and marked QT prolongation; ST segment changes, atrial fibrillation; junctional rhythm |
| Pentamidine | Structurally similar to procainamide; binds avidly to cardiac tissue, which may produce ECG changes after discontinuation of therapy | QTc prolongation with associated torsade de pointes; T wave abnormalities and ST segment changes |
| Erythromycin | Metabolic alterations occurring in ischemia or after digitalis administration may enhance the loss of potassium | QT prolongation |
| Quinine | Quinine is the l-isomer of quinidine; the cardiovascular effect of quinine is estimated at1/3 that of quinidine | PR prolongation, QRS widening, QT prolongation, prominent U waves; overdose can cause asystole and ventricular tachycardia including torsade de pointes |
| Amantadine | Chemical structure and pharmacologic properties are similar to TCAs: hypotension, bradycardia, and arrhythmias | Sinus tachycardia, PR, QRS, and QT prolongation, ectopic activity. Cardiac arrest, including ventricular tachycardia and torsade de pointes, may appear as long as 36 hours after ingestion of toxic doses |
| Doxorubicin | Dose-dependent irreversible cardiomyopathy may be due to free radical formation with release of cardiac histamine and other vasoactive substances; may also directly affect calcium ion channels, producing irreversible cell damage due to intracellular calcium overload | Acute: supraventricular arrhythmias (rarely clinically significant); chronic: decreased QRS voltage |
| Lithium | Artial displacement of intracellular potassium sinus node dysfunction with bradycardia | T wave abnormalities; first degree AV block, paroxysmal left bundle branch block; at toxic doses, may see QTc prolongation |
| TCAs | Possess anticholinergic activity, exert a direct myocardial depressant activity, and block noradrenaline reuptake in the heart | Similar to those produced by the phenothiazines and class I antiarrhythmics: increased heart rate, prolongation of the PR interval, intraventricular conduction disturbances, increase in QTc interval, and flattening of T waves |
| Carbamazepine | Shortens action potential duration | Sinus bradycardia, AV conduction disturbances may occur with therapeutic or modestly elevated plasma concentrations; tachycardia occurs in overdose; older patients or those with pre-existing conduction abnormalities are particularly vulnerable |
| Probucol | Unknown mechanism | Reversible prolongation of QTc interval; Probucol is eliminated slowly, so abnormality may persist after discontinuation of therapy |
| Cotrimoxazole | Unknown mechanism | QT prolongation |
Michael D. Furnas is a cardiology technician and pacemaker education provider in Omaha, Nebraska.
Copyright © 1997, American Society of Consultant
Pharmacists, Inc. All rights reserved.